Substance abuse has become a major concern in the United States. 17% of Americans meet the diagnostic criteria for some form of substance dependence (excluding tobacco dependence). Alarmingly, 90% of addicted individuals relapse, even after a prolonged period of abstinence. Several factors initiate relapse to drug seeking in addicted individuals. The most well documented factors include exposure to environmental stressors, exposure to drug-associated cues, and exposure to the drug itself. The clinical literature suggests that sleep deprivation is another factor that affects relapse in humans. Sleep deprivation (SD) is ubiquitous in our society, yet, the effects of this factor on relapse have received relatively little attention in the laboratory. In fact, while progress has been made in identifying the neural mechanisms by which stress, cue exposure, and drug exposure instigate relapse, the mechanisms by which SD elicits relapse remain uninvestigated. Reward circuits known to be involved drug-seeking behavior are also involved in sleep regulation, and, thus, are affected by SD. Even so, it remains unclear how sleep and waking systems of the brain may interface with these reward pathways to influence the acquisition and reinstatement of drug seeking behavior. Preliminary data show that just 4 to 8 hours of acute SD serves to augment drug-induced relapse in rats. The proposed studies will expand upon these findings, and evaluate whether chronic SD, akin to levels commly experienced by humans, facilitates acquisition and reinstatement of cocaine seeking in rats (Specific Aim I). In addition, the mechanisms by which chronic SD augments the acquisition and reinstatement of cocaine seeking will be investigated (Specific Aim II). Specifically, the roles of nucleus accumbens (NAc) dopamine (DA), plasma corticosterone (CORT), and the bed nucleus of the stria terminalis (BNST) will be investigated. The role of the NAc in the processing of natural rewards and drugs of abuse is well documented. Therefore, the NAc DAergic response to an acute intravenous (IV) administration of cocaine will be measured in SD rats. Similarly, CORT has been shown to play a permissive role in relapse induced by food deprivation. Therefore, the plasma CORT response to the acute IV administration of cocaine will also be assessed following chronic SD. Finally, the BNST has been shown to mediate stress-induced relapse. Sleep deprivation imposes a significant amount of stress, and may therefore initiate relapse via the same mechanism. Consequently, it will be determined whether ibotenic acid lesions of the BNST abolish the facilitative effects of chronic SD on acquisition and reinstatement of cocaine seeking.